This application is an application under 35 U.S.C. Section 371 of International Application Number PCT/FR99/03273 filed on Dec. 23, 1999.
The present invention relates to a process for preparing biphenyl type aromatic thioethers.
More precisely, the invention relates to the preparation of an aromatic compound comprising a concatenation of at least two phenyl groups at least one of which carries a thioether group.
More particularly, the invention relates to the preparation of 4-chloro-4xe2x80x2-thiomethyldiphenyether.
When a functional group is to be introduced into a biphenyl type molecule, there is a problem with introducing a functional group into only one of the benzene rings.
The present invention aims to provide a process that consists of introducing at least one thioether group into one of the phenyl groups.
It has now been discovered, and this forms the subject matter of the present invention, a process for preparing a biphenyl type aromatic thioether, characterized in that a diazonium salt of a biphenyl type aromatic compound is reacted with a disulphide type sulphur-containing compound in an aqueous medium in the presence of an effective quantity of a coupling catalyst.
The term xe2x80x9cbiphenyl type aromatic thioetherxe2x80x9d means a concatenation of two phenyl groups connected together wherein at least one of the benzene rings carries a thioether function.
In a preferred variation of the process of the invention, the thioether is prepared using a process that associates preparation of the diazonium salt from the corresponding aromatic amine then, without separation, carrying out the reaction with the sulphur-containing compound.
In accordance with the process of the invention, a biphenyl type aromatic amine can be used as the starting compound; in a first step, it is transformed into a diazonium salt.
The term xe2x80x9cbiphenyl type aromatic aminexe2x80x9d means a concatenation of two phenyl groups connected together wherein at least one of the benzene rings carries an amine function.
The starting aromatic amine can be represented by the following general formula (1): 
in which formula (I):
R1 represents a hydrogen atom or a substituent R;
Z represents:
a covalent bond;
an alkylene or alkylidene group containing 1 to 4 carbon atoms, preferably a methylene or isopropylidene group;
a group B which may be one of the following atoms or groups:
xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOOxe2x80x94
xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, 
xe2x80x83in which formulae, R2 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, or a phenyl group.
In formula (I), one or both benzene rings can be substituted, meaning that in the biphenyl type starting substrate, at least one of the 5 hydrogen atoms of the aromatic ring can be replaced by an atom other than a hydrogen atom. In particular, it can be a halogen atom, carbon, oxygen or nitrogen.
Group R1 represents a hydrogen atom or any other group R.
Group R can have any nature provided that it does not interfere with the diazotisation reaction.
Non-limiting examples of substituents that can be cited are given below:
a linear or branched alkyl group, preferably containing 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms;
a linear or branched alkenyl group preferably containing 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms;
a linear or branched halogenoalkyl group preferably containing 1 to 4 carbon atoms, and 1 to 9 halogen atoms;
a cycloalkyl group containing 3 to 7 carbon atoms, preferably a cyclohexyl group;
a phenyl group;
a hydroxyl group;
a NO2group;
a R3xe2x80x94Oxe2x80x94 alkoxy group or R3xe2x80x94Sxe2x80x94 thioether group where R3 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, or a phenyl group;
a xe2x80x94Nxe2x80x94(R2)2 group where groups R2, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, or a phenyl group;
a xe2x80x94NHxe2x80x94COxe2x80x94R2 group where R2 has the meaning given above;
a carboxyl group or R2xe2x80x94Oxe2x80x94COxe2x80x94 derivative, where group R2 has the meaning given above;
an acyloxy or aroyloxy group R3xe2x80x94COxe2x80x94Oxe2x80x94, where group R3 has the meaning given above;
a B(OR3)2 group, where group R3 has the meaning given above;
a halogen atom, preferably a fluorine atom;
a CF3 group;
two groups R can together form an alkylenedioxy group containing 1 to 4 atoms in the alkylene group, preferably a methylenedioxy or ethylenedioxy group.
Preferred groups R that can be cited are a halogen atom, preferably a fluorine, chlorine or bromine atom or a halogenoalkyl group, preferably perfluoroalkyl; a hydroxyl group; an alkyl or alkoxy group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms; an amino group or an amino group substituted with one or two alkyl groups containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Preferred compounds are those with formula (I) where R1 represents a fluorine atom or a chlorine atom and Z represents an oxygen atom.
In accordance with the process of the invention, in a first step the diazonium salt of the biphenyl type aromatic amine preferably with formula (I) is prepared.
To this end, to transform the amino group into a diazonium group, the starting substrate is reacted with an acid. While it is possible to use an acid such as sulphuric acid, it is preferable to use a hydrogen acid to put the amine group into the halohydrate salt form.
Thus, the starting substrate preferably with formula (I) is preferably reacted with hydrochloric acid or hydrobromic acid.
The quantity of acid used is such that the mole ratio between the number of H+ ions and the number of moles of substrate is in the range 2.0 to 2.5, preferably in the range 2.0 to 2.2.
In the next step, the diazonium salt is prepared by reacting the biphenyl type aromatic amine in the halohydrate form with a diazotisation reactant that is any source of NO+.
Thus it is possible to start from nitrogen dioxide NO2, nitrogen trioxide N2O3, nitrogen tetroxide N2O4, nitric oxide NO associated with an oxidising agent such as nitric acid, nitrogen dioxide or oxygen. When the reactant is a gas under the reaction conditions, it is bubbled into the mediun.
It is also possible to use a nitrous acid, a nitrosyl sulphide or a nitrose or a nitrous salt, preferably an alkali metal salt, more preferably a sodium salt.
It is also possible to use alkyl nitrites, more particularly those with formula (II):
Raxe2x80x94ONOxe2x80x83xe2x80x83(II)
in which formula (II), Ra represents a linear or branched alkyl group containing 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms.
Advantageously, sodium nitrite is used.
The quantity of diazotisation reactant used can vary widely. When it is expressed as the mole ratio of the aromatic aminel diazotisation reactant defined as NO+, it is at least equal to the stoichiometric quantity but preferably, it is used in an excess of up to 120% of the stoichiometric quantity, preferably in the range 100% to 120%.
Regarding the concentration of the aromatic amine substrate in the reaction medium, it is preferably in the range 0.5 to 2.5 mol/l, more preferably about 1 mol/l.
The amine halohydrate is prepared by simply mixing the starting amine and the acid.
The reaction is advantageously carried out at a temperature in the range 50xc2x0 C. to 100xc2x0 C.
The diazotisation reactant is then added, preferably slowly in fractions or continuously.
Regarding the temperature of the diazotisation reaction, this is generally a low temperature, advantageously in the range xe2x88x9210xc2x0 C. to 20xc2x0 C., preferably in the range 0xc2x0 C. to 10xc2x0 C.
In the process of the invention, the sulphur-containing compound is reacted with the diazonium salt obtained, which preferably has the following formula (III): 
in which formula (III):
X represents a halogen atom X, preferably a chlorine or bromine atom, a HSO4xe2x88x92 group or a SO4= group;
R1 and Z have the meanings given above;
n equals 1 or 2.
The sulphur-containing compound used preferably has the following formula (IV):
R4xe2x80x94Sxe2x80x94Sxe2x80x94R5xe2x80x83xe2x80x83(IV)
in said formula (IV):
R4 and R5, which may be identical or different, represent a hydrocarbon group containing 1 to 24 carbon atoms, which can be a saturated or unsaturated, linear or branched aliphatic acyclic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group, or a linear or branched, saturated or unsaturated aliphatic group carrying a cyclic substituent.
The sulphur-containing compound used in the process of the invention has formula (IV) where R4 and R5 can have a number of meanings. Different, non-limiting, examples will be given below.
With compounds with formula (IV), R4 and R5 preferably represent a saturated or unsaturated, linear or branched acyclic aliphatic group preferably containing 1 to 24 carbon atoms, comprising one or more unsaturated bonds in the chain, generally 1 to 3 unsaturated bonds which may be simple double bonds or conjugated double bonds or triple bonds.
More particularly, R4 and R5 represent a linear or branched alkyl, alkenyl, or alkadienyl group preferably containing 1 to 12 carbon atoms.
R4 and R5 represent a linear or branched halogenoalkyl group preferably containing 1 to 12 carbon atoms, more preferably 1 to 4 carbon atoms, and 3 to 25 halogen atoms.
The hydrocarbon chain can optionally be:
interrupted by a functional atom or group; groups B cited above may be cited in this respect;
and/or carry the following substituents:
xe2x80x94OH, xe2x80x94COR3, xe2x80x94COOR2, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3,
where R2, which may be identical or different, and R3 have the meaning given above.
Groups R4 and R5 can represent a halogenoalkyl group, preferably perhalogenoalkyl, or a halogenoalkenyl group.
In formula (IV), the saturated or unsaturated linear or branched aliphatic acyclic group can optionally carry a cyclic substituent. The term xe2x80x9ccyclexe2x80x9d means a saturated, unsaturated or aromatic carbocyclic or heterocyclic cycle.
The aliphatic acyclic group can be bonded to the cycle by a covalent bond or by a group B as cited above.
Examples of cyclic substituents that can be envisaged are cycloaliphatic, aromatic or heterocyclic substituents, in particular cycloaliphatic substituents containing 6 carbon atoms in the cycle or benzenic substituents, such cyclic substituents themselves optionally carrying one or more substituents.
Examples of such groups that can be mentioned are the benzyl group.
In general formula (IV), R4 and R5 can represent a monocyclic carbocyclic group. The number of carbon atoms in the cycle can vary widely from 3 to 8 carbon atoms, but is preferably 5 or 6 carbon atoms.
The carbocyle can be saturated or may comprise 1 or 2 unsaturated bonds in the cycle, preferably 1 or 2 double bonds.
Preferred examples of groups R4 and R5 that can be cited are cyclohexyl or cyclohexeneyl groups.
When R4 or R5 represents a saturated or unsaturated monocyclic carbocyclic group, one or more of the carbon atoms of the cycle may be replaced by a heteroatom, preferably oxygen, nitrogen or sulphur or by a fimctional group, preferably carbonyl or ester, leading to a monocyclic heterocyclic compound. The number of atoms in the cycle can be in the range 3 to 8 atoms, preferably 5 or 6 atoms.
Groups R4 and R5 can also be polycyclic carbocyclic, preferably bicyclic, meaning that at least two cycles have two carbon atoms in common. With polycyclic groups, the number of carbon atoms in each cycle is in the range 3 to 6: the total number of carbon atoms is preferably 7 .
Groups R4 and R5 can also be polycyclic heterocyclic, preferably bicyclic, which means that at least two cycles have two atoms in common. In this case, the number of atoms in each cycle is in the range 3 to 6, more preferably 5 or 6.
Groups R4 and R5 preferably represent an aromatic carbocyclic group, in particular benzenic or a concatenation of 2 or 3 benzene rings separated by atoms or groups B as defined above.
Examples of groups R4 and R5 with formula (IV) that can more particularly be mentioned are phenyl groups.
R4 and R5 can also represent a polycyclic aromatic hydrocarbon group; the cycles can between them form ortho-condensed or ortho- and peri-condensed systems. More particularly, the group can be the naphthyl group.
In general formula (IV), R4 and R5 can also represent an aromatic heterocyclic group in particular comprising 5 or 6 atoms in the cycle, wherein 1 or 2 are heteroatoms such as nitrogen, sulphur or oxygen.
Illustrative examples of heterocyclic groups that can be cited are tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, furyl, thienyl, pyrrolyl and pyridyl.
R4 and R5 can also represent a polycyclic aromatic heterocyclic group defined as either a group constituted by at least two aromatic or non aromatic heterocycles containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri-condensed systems, or a group constituted by at least one aromatic or non aromatic hydrocarbon cycle and at least one aromatic or non aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems.
Illustrative examples of polycylic groups that can be cited are: isoquinolyl, quinolyl, naphthyridinyl, benzofuranyl and indolyl.
It should be noted that if group R4 and R5 comprises a cycle, that cycle may carry a substituent. The nature of the substituent is irrelevant as long as it does not interfere with the desired product. The substituents are of the same nature as R.
Preferred examples of groups R4, R5 that can be cited are linear or branched alkyl groups containing 1 to 4 carbon atoms, 2-carboxyethyl, cyclohexyl, phenyl, benzyl, benzoyl, pyridyl, etc.
The process is readily carried out using a number of sulphur-containing compounds.
Preferred examples of disulphide type sulphur-containing compounds that can be mentioned are:
dimethyldisulphide;
diethyldisulphide;
di-n-propyldisulphide;
diisopropyldisulphide;
di-n-butyldisulphide;
diisobutyldisulphide;
di-sec-butyldisulphide;
di-tert-butyldisulphide;
diisoamyldisulphide;
di-n-hexyldisulphide;
di-tert-heptyldisulphide;
di-n-undecyldisulphide;
distearyldisulphide;
diallyldisulphide;
dicyclohexyldisulphide;
diphenyldisulphide;
dibenzyldisulphide
dibenzoyldisulphide;
dithiopyridine;
dithioglycolic acid.
Preferred compounds from the list cited above are dialkyldisulphides preferably containing 1 to 4 carbon atoms in the alkyl portion.
The quantity of sulphur-containing compound is such that said mole ratio is preferably in the range 1 to 1.5.
The coupling reaction is carried out in an aqueous medium. The quantity of water present in the reaction medium generally represents 100% to 500% by weight of the aromatic amine.
In a variation, the process of the invention consists of adding an organic solvent which is inert under the reaction conditions.
Examples of organic solvents that can be cited are saturated aliphatic monocarboxylic acids, more particularly formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pentanoic acid and 2-methylbutanoic acid.
Acetic acid is the preferred saturated aliphatic monocarboxylic acid.
It is also possible to use a solvent such as acetone or dimethylformamide.
The quantity of organic solvent used, expressed as the weight of starting amine, is advantageously in the range 100% to 1000%, preferably in the range 200% to 500%.
In the process of the invention, the diazonium salt, preferably with formula (III), is reacted with the sulphur-containing compound, preferably with formula (IV): the reaction is carried out in the presence of a coupling catalyst.
The coupling catalyst is a catalyst comprising at least one metallic element selected from the 4th and 5th period of groups IIIA, IVA, VA, VIA, VIIA, VIII, IB and IIB of the periodic table.
Preferred metals that can be cited are: copper, iron, cobalt, nickel, palladium and platinum.
The elements are defined in the periodic table published in the xe2x80x9cBulletin de la Socixc3xa9txc3xa9Chimique de France, No.1 (1966).
The metallic elements can also be supplied in the form of a zero metal or an inorganic derivative such as an oxide or hydroxide. It is possible to use a mineral salt, preferably a nitrate, sulphate, oxysulphate, halide, oxyhalide, silicate, carbonate or an organic derivative, preferably a cyanide, oxalate, acetylacetonate; an alcoholate, more preferably a methylate or ethylate; or a carboxylate, more preferably an acetate. It is also possible to use complexes, in particular chlorine-containing or cyanide-containing complexes of said metals and/or alkali metals, preferably sodium or potassium, or ammonium.
More specific examples of palladium catalysts that can be cited are palladium (II) chloride, hydrated palladium (II) nitrate, dihydrated palladium (II) sulphate, palladium (II) acetate, ammonium tetrachloropalladate (II), potassium hexachloropalladate (IV), and palladium (II) tetrakisphenylphosphine.
Platinum catalysts that can be mentioned include platinum (II) chloride, ammonium tetrachlorplatinate (II), ammonium hexachloroplatinate (IV), hydrated sodium tetrachloroplatinate (IV), hexahydrated sodium hexachloroplatinate (IV), potassium hexachloroplatinate (IV), and hexahydrated chloroplatinic acid.
Nickel or cobalt catalysts that can be cited include nickel (II) bromide and chloride and cobalt (II) chloride or bromide.
The catalyst of choice used in the process of the invention is copper-based.
Examples of catalysts that can be cited are copper metal or organic or inorganic copper I or copper II compounds.
Preferably, catalysts based on copper 0 and I are used.
Non limiting examples of copper compounds that can be cited are cuprous bromide, cupric bromide, cuprous iodide, cuprous chloride, cupric chloride, basic copper II carbonate, cuprous nitrate, cupric nitrate, cuprous sulphate, cupric sulphate, cuprous sulphite, cuprous oxide, cuprous acetate, cupric acetate, cupric trifluoromethylsulphonate, cupric hydroxide, copper I methylate, copper II methylate, and chlorocupric methylate with formula ClCuOCH3.
The quantity of catalyst used, expressed as the ratio of the weight of diazonium salt is generally in the range 0.1 to 20 mole %, preferably 1% to 10%.
The coupling reaction between the diazonium salt preferably with formula (III) and the sulphur-containing compound is advantageously carried out at a temperature in the range 0xc2x0 C. to 120xc2x0 C., preferably in the range 80xc2x0 C. to 100xc2x0 C.
In general, the reaction is carried out at atmospheric pressure, but lower or higher pressures may also be suitable. Autogenous pressure is employed when the reaction temperature is higher than the boiling temperature of the reactants and/or products.
In a preferred variation of the process of the invention, the process of the invention is carried out in a controlled atmosphere of inert gas. A rare gas atmosphere can be established, preferably argon, but nitrogen is more economical.
The reaction is continued until the diazonium salt is completely transformed. The reaction progress can be monitored using any conventional analytical technique such as gas chromatography or high performance liquid chromatography.
The reaction period is generally short, of the order of 30 min to 2 hours.
From a practical viewpoint, the two reactants are brought together in any order. In a preferred variation, the sulphur-containing compound is preferably added to the diazonium salt, followed by the catalyst.
At the end of the reaction, two phases are obtained; the aqueous phase comprises all of the salts formed and the organic phase comprises, in addition to any excess reactants, the desired compound which preferably has formula (VI): 
in which formula (VI), R1, R4 and Z have the meanings given above.
The desired product is recovered from the organic phase using conventional techniques. By way of illustration, it is possible to add an organic solvent, for example isopropyl ether or an alkane such as methylcyclohexane, to extract all of the organic compounds and then, from this organic phase, to separate the compound using the usual separation techniques such as distillation or crystallisation from a suitable solvent, preferably an alcohol, more particularly methanol or isopropanol.